Neurodegenerative diseases, cancer and infections of the brain become more prevalent as populations become older. However, despite the relatively high blood flow in the brain, the brain is probably one of the least accessible organs for the delivery of active pharmacological compounds. There are two physiological barriers separating the brain from free supply via the blood system. The first barrier is the blood-brain barrier (BBB) and the second barrier is the blood-cerebrospinal fluid barrier (BCSFB).
Since the surface area of the human BBB is estimated to be 5000 times greater than that of the BCSFB, the BBB is considered to be the main barrier controlling the uptake of molecules such as drugs into the brain parenchyma and the target for delivering drugs to the brain. The BBB is defined by the microvasculature of the brain, which consists of a monolayer of polarized endothelial cells connected by complex tight junctions. The function of the BBB is dynamically regulated by various cells, including astrocytes, neurons and pericytes.
The endothelial cells are separated from these other cells by a basal lamina, whose components such as type IV collagen, laminin, fibronectin and heparan sulfate may be involved in drug transport, as some of them are negatively charged.
The BBB is characterized by complex tight junctions between the endothelial cells of the brain capillaries known for their low endocytic activity. However, the BBB also contains a number of specific transport and enzyme systems that regulate molecular traffic across the blood capillaries. The barrier and its selective transport system also play an important role in the homeostatic regulation of the brain microenvironment necessary for stable and coordinated activity of neurons. Circulating molecules can cross the BBB via the: (i) lipid mediated transport of small molecules by free diffusion and (ii) catalyzed transport. The latter includes carrier-mediated transport (CMT) for low molecular weight nutrient or receptor-mediated transport (RMT) for circulating peptides and plasma proteins. The BBB is therefore the major obstacle to drugs that may combat diseases affecting the central nervous system (CNS), from getting within the proximity of affected neurons.
Several strategies for delivering drugs to the CNS have been developed, in order to enhance the capacity of therapeutic molecules to cross the BBB: (i) an injectable composition comprising compounds that permeate the BBB; (ii) the drug of choice is covalently coupled to a vector for receptor-mediated or adsorption-mediated trans-cytosis; and (iii) the drug itself is modified in such a way that enables its permeation through the BBB.
These strategies have undesired side effects such as the non-selective overall enhanced permeability of the BBB i.e. impairment of the BBB function; interference with the therapeutic capacity of the drug itself. Furthermore, modifications of drugs do not necessarily contribute to the specificity of the treatment and may even reduce it by directing the compounds to tissues and organs that are not the “natural” target of the drug.